Background <p>Melanoma is a highly aggressive skin cancer with a high mortality rate. Although targeted therapies and immunotherapies have advanced, the prognosis for advanced melanoma remains poor. The identification of novel molecular biomarkers is thus crucial for early diagnosis and prognosis prediction. The transcription factor TBX19 has been linked to various biological processes, but its role in melanoma pathogenesis is not well defined.</p> Methods <p>We analyzed the expression patterns and the diagnostic and prognostic significance of TBX19 in melanoma using data from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) between TBX19 high- and low-expression groups were identified and subjected to functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction (PPI) network analysis. The relationship between TBX19 expression and immune cell infiltration was evaluated. Furthermore, we investigated TBX19-associated signaling pathways and drug sensitivity using the Genomics of Drug Sensitivity in Cancer (GDSC) database. The functional role of TBX19 was validated through in vitro and in vivo experiments.</p> Results <p>TBX19 expression was significantly downregulated in melanoma tissues, and this downregulation was associated with an unfavorable prognosis. Low TBX19 expression was an independent risk factor for poorer overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). Functional enrichment analysis indicated that TBX19-related DEGs were involved in processes such as keratinization and immune response. TBX19 expression showed a positive correlation with the infiltration of T helper cells and Tcm cells, but a negative correlation with mast cell infiltration among others. Moreover, TBX19 expression was linked to the epithelial-mesenchymal transition (EMT) and the RAS-Mitogen-Activated Protein Kinase (RAS-MAPK) signaling pathway, and it influenced sensitivity to several anticancer drugs. In vitro experiments demonstrated that TBX19 knockdown promoted proliferation, migration, and invasion in A375 cells, upregulated cyclin D1, cyclin E1, N-cadherin, and vimentin, and downregulated E-cadherin. Conversely, TBX19 overexpression yielded opposite effects in SK-MEL-1 cells. An in vivo xenograft model confirmed that TBX19 knockdown accelerated tumor growth.</p> Conclusions <p>TBX19 functions as a tumor suppressor in melanoma, modulating tumor progression, immune infiltration, and drug responses. Our findings reveal TBX19 as a potential diagnostic biomarker and therapeutic target, offering new insights into the molecular mechanisms of melanoma.</p>